The complex karyotype landscape in chronic lymphocytic leukemia allows the refinement of the risk of Richter syndrome transformation

Abstract

Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural abnormalities) or high-CK (CK with C5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter reallife retrospective study to test its prognostic impact.
 Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q-/TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; while mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (p<0.0001).
 We herein demonstrated that CK landscape at CLL diagnosis allows to refine the risk of RS transformation and we recapitulated clinico-biological variables into a prognostic model.

Continuous treatment with Ibrutinib in 100 untreated patients with TP53 disrupted chronic lymphocytic leukemia: A real‐life campus CLL study

“…1 In CLL, TP53 disruption is a negative prognostic and predictive biomarker, associated with genome complexity, early relapse, and shorter survival after chemoimmunotherapy, as well as Richter syndrome (RS) transformation. [1][2][3] In addition, this adverse genetic feature has been associated with an increased risk of treatment failure in relapsed patients treated with BTK inhibitor [4][5][6] and with fixed duration venetoclax-based therapy in previously untreated and relapsed/refractory CLL patients. 7,8 While ibrutinib has been shown to be highly active and able to induce long-lasting remission in CLL with unfavorable features, such as unmutated IGHV status or 11q22-23 deletion, 4 patients with TP53 disruption were excluded from pivotal frontline trials.…”

Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents

“…Moreover, IGHV4-39 gene usage has been shown to carry a 24-fold increased risk of RT and when combined with stereotyped BCR (SUBSET 8) in the same patient, it showed a 5 year risk of RT of 68.7% [6]. Another recently noted point is that CLL patients with a complex karyotype at diagnosis seem to have the highest risk and shortest time to Richter transformation [44,45].…”

Clonal Evolution of High-Risk Chronic Lymphocytic Leukemia: A Contemporary Perspective

“…( 48 ). Recent work also demonstrates complex karyotype as a risk factor for the development of RS ( 31 ), with complex karyotype representing another consequence of genomic instability.…”

“…These prospectively validated, conventional biomarkers of high-risk CLL, particularly del(17p) as well as IGHV and TP53 mutational status, continue to find relevance in contemporary clinical practice, and are featured within widely used prognostic indices such as the CLL International Prognostic Index (CLL-IPI) ( 28 ). Finally, the importance of complex karyotype identified by chromosome banding analysis and/or genomic microarrays has recently arisen, with complex karyotype conferring inferior outcome independently of the CLL-IPI ( 29 – 31 ).…”